A Phase II, Study to Determine the Preliminary Efficacy of Novel Combinations of Treatment in Patients With Platinum Refractory Extensive-Stage Small-Cell Lung Cancer

Inclusion criteria (applicable to all arms)

1. Adults with histologically or cytologically documented ED SCLC who have demonstrated progressive disease either during first-line platinum-based chemotherapy (platinum refractory) or within 90 days of completing platinum based-chemotherapy (platinum resistant) and have not received further treatment.
2. Brain metastases must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment.
3. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline (per RECIST v 1.1 guidelines)
4. Life expectancy of at least 8 weeks.
5. WHO/ ECOG PS of 0-1 at enrollment.

Inclusion criteria (Arm A specific)

1. Body weight >30 kg.
2. No prior exposure to immune mediated therapy, excluding therapeutic anticancer vaccines.

Inclusion criteria (Arm B specific) • Able and willing to swallow oral medication.

Inclusion criteria (Arm C specific)

• Able and willing to swallow oral medication.

Exclusion criteria (applicable to all arms):

1. Participation in another clinical study, major surgery, radiation therapy within 28 days.
2. Any condition that, in the opinion of the Investigator, would interfere with the evaluation of the IP or interpretation of patient safety or study results.
3. Uncontrolled intercurrent illness, including but not limited to interstitial lung disease.
4. History of another primary malignancy, leptomeningeal carcinomatosis or spinal cord compression.

Exclusion criteria (Arm A specific)

1. Active autoimmune disease, including a paraneoplastic syndrome.
2. Active or prior documented autoimmune or inflammatory disorders.
3. Any unresolved toxicity (CTCAE Grade >2) from previous anticancer therapy.
4. Active infection including tuberculosis, HIV, Hepatitis B or C.

Exclusion criteria (Arm B specific)

1. Prior exposure to any WEE1 inhibitors.
2. Products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4. Co-administration of rosuvastatin, atorvastatin, simvastatin and lovastatin, aprepitant or fosaprepitant or any herbal preparations. Grapefruit and Seville oranges should be avoided while taking AZD1775.
3. Any known hypersensitivity or contraindication to IP or CBDP.
4. QTcF > 470 msec or congenital long QT syndrome.
5. Any current or within 6 months cardiac diseases NYHA ≥ Class 2: unstable angina pectoris, congestive heart failure, acute MI, conduction abnormality not controlled with pacemaker or medication, significant ventricular or supraventricular arrhythmias.
6. A recent history of Torsades de pointes.

Exclusion criteria (Arm C specific)

1. Cytotoxic chemotherapy within 21 days of Cycle 1 Day 1 is not permitted
2. Previous treatment with a PARP inhibitor (including olaparib) or ATR inhibitor
3. Concomitant use of known strong CYP3A inhibitors and moderate CYP3A inhibitors
4. Concomitant use of known strong and moderate CYP3A inducers
5. Persisting (> 4 weeks) severe pancytopenia due to previous therapy
6. Cardiac dysfunction
7. Refractory nausea and vomitting, chronic gastrointenstinal diseases or previous significant bowel resection
8. Patients with uncontrolled seizures
9. Intenstinal obstruction or CTCAE grade 3 or grade 4 GI bleeding within 4 weeks before dosing